Intravenous drug use continues to be a major public health problem which is a significant vector for the spread of AIDS with the co-use of cocaine and opiate agonists increasing and recentlyshown to decrease the likelihood of a successful treatment outcome. This application proposes the continuation of research into the mechanisms underlying the self-administration of cocaine and heroin and the potentiation of the neurochemical effects of cocaine by heroin. During this last funding period, heroin was shown to potentiate the effects of cocaine on the increase in nucleus accumbens extracellular fluid levels of dopamine at self- administered doses on the ascending limb of the dose-intake relationship. It was also found that the effect of the combination of these two drugs on self-administration was both additive in an isobolographic analysis and synergistic in a choice procedure. In addition, it was shown that ventral pallidal and ventral tegmental area u opioid receptors are important in the effects upon self-administration since alkylation of these receptors shifted dose-intake relationships to that of cocaine alone. Experiments are proposed to define the role of glutamate (Glu) and v-aminobutyric acid (GABA) neurons in the medial prefrontal cortex, nucleus accumbens, ventral pallidum and ventral tegmental area in the effects upon self-administration and upon the neurochemical potentiation. This involvement of Glu and GABA releasing neurons will beassessed with microdialysis techniques, laser capture microdissection, gene expression profiling and protein measurements of discrete neuronal subgroups to characterizethe neuro-adaptations that occur in response to the self-administration of cocaine/heroin combinations. These data will be used to expand upon a model of opiate-stimulant interactions that will be further tested through the use of intracerebral injections of specific GABA and Glu receptor agonists and antagonists to identify and verify the participation of neurons containing the critical opiate receptors responsible for the effects upon self-administration of the combination and the neurochemical potentiation of cocaine by heroin. Relevance: The concurrent use of COC and opiate combinations has increased since the 1970's and now represents a significant subset of intravenous drug abusers. This co-abuse has negative consequences since a high level of COC use at intake has been reported to decreasethe likelihood of a positive treatment outcome for opiate addicts. This application proposes the continuation of research into the mechanisms underlying the self-administration of cocaine and heroin combinations and the potentiation of the neurochemical effects of cocaine by heroin demonstrated in this last funding period. Clearly, knowledge of the mechanisms of this enhancement could be helpful in the development of therapeutic strategies to treat this co-abuse.